Field
The present invention relates to a composition comprising β-hydroxy-β-methylbutyrate (HMB) and adenosine-5′-triphosphate (ATP), and methods of using a combination of HMB and ATP to improve strength and power, improve muscle mass and prevent or lessen typical declines in performance characteristic of overreaching.
Background
HMB
The only product of leucine metabolism is ketoisocaproate (KIC). A minor product of KIC metabolism is β-hydroxy-β-methylbutyrate (HMB). HMB has been found to be useful within the context of a variety of applications. Specifically, in U.S. Pat. No. 5,360,613 (Nissen), HMB is described as useful for reducing blood levels of total cholesterol and low-density lipoprotein cholesterol. In U.S. Pat. No. 5,348,979 (Nissen et al.), HMB is described as useful for promoting nitrogen retention in humans. U.S. Pat. No. 5,028,440 (Nissen) discusses the usefulness of HMB to increase lean tissue development in animals. Also, in U.S. Pat. No. 4,992,470 (Nissen), HMB is described as effective in enhancing the immune response of mammals. U.S. Pat. No. 6,031,000 (Nissen et al.) describes use of HMB and at least one amino acid to treat disease-associated wasting.
HMB is an active metabolite of the amino acid leucine. The use of HMB to suppress proteolysis originates from the observations that leucine has protein-sparing characteristics. The essential amino acid leucine can either be used for protein synthesis or transaminated to the α-ketoacid (α-ketoisocaproate, KIC). In one pathway, KIC can be oxidized to HMB. Approximately 5% of leucine oxidation proceeds via the second pathway. HMB is superior to leucine in enhancing muscle mass and strength. The optimal effects of HMB can be achieved at 3.0 grams per day, or 0.038 g/kg of body weight per day, while those of leucine require over 30.0 grams per day.
Once produced or ingested, HMB appears to have two fates. The first fate is simple excretion in urine. After HMB is fed, urine concentrations increase, resulting in an approximate 20-50% loss of HMB to urine. Another fate relates to the activation of HMB to HMB-CoA. Once converted to HMB-CoA, further metabolism may occur, either dehydration of HMB-CoA to MC-CoA, or a direct conversion of HMB-CoA to HMG-CoA, which provides substrates for intracellular cholesterol synthesis. Several studies have shown that HMB is incorporated into the cholesterol synthetic pathway and could be a source for new cell membranes that are used for the regeneration of damaged cell membranes. Human studies have shown that muscle damage following intense exercise, measured by elevated plasma CPK (creatine phosphokinase), is reduced with HMB supplementation within the first 48 hrs. The protective effect of HMB lasts up to three weeks with continued daily use. Numerous studies have shown an effective dose of HMB to be 3.0 grams per day as CaHMB (calcium HMB) (˜38 mg/kg body weight-day−1). This dosage increases muscle mass and strength gains associated with resistance training, while minimizing muscle damage associated with strenuous exercise (34) (4, 23, 26). HMB has been tested for safety, showing no side effects in healthy young or old adults. HMB in combination with L-arginine and L-glutamine has also been shown to be safe when supplemented to AIDS and cancer patients.
Recently, HMB free acid, a new delivery form of HMB, has been developed. This new delivery form has been shown to be absorbed quicker and have greater tissue clearance than CaHMB. The new delivery form is described in U.S. Patent Publication Serial No. 20120053240 which is herein incorporated by reference in its entirety.
ATP
Adenosine-5′-triphosphate (ATP) has long been known as the chemical energy source for tissues including muscle (19). Intracellular ATP concentrations (1-10 mM) are quite high in contrast to extracellular concentrations (10-100 nM) and therefore release of ATP from cells such as erythrocytes and muscle is strictly controlled. More recently extracellular effects of ATP, acting through purinergic receptors found in most cell types, have been elicited (20). Several extracellular physiological functions of ATP have been described including vasodilation (21), reduced pain perception (22), and as a neurotransmission cotransmitter (23, 24). Importantly, small and transient increases in vascular ATP in muscle can cause vasodilation and an increase in blood flow to the muscle (25). Therefore, if ATP increases blood flow to muscle, especially during periods of strenuous resistance training, substrate availability would be improved and removal of metabolic waste products would be better facilitated. Ellis et al recently reviewed the studies supporting the role of ATP in increasing muscle blood flow through purinergic signaling and neurotransmission (25).
ATP has been shown to have an inotrophic effect ATP on cardiac muscle (26, 27). Another study supporting systemic effects of ATP demonstrated that oral administration of ATP to rabbits for 14 days resulted in a reduction in peripheral vascular resistance, improvement of cardiac output, reduction of lung resistance, and increased arterial PaO2 (28).
Adenosine, resulting from the degradation of ATP, may also act as a signaling agent through purinergic receptors (29) or may be degraded by adenosine deaminase (30). Adenosine acting through purinergic receptors can essentially mimic the effects of ATP (29). Adenosine infusion into muscle results in increased nitric oxide formation and similar vascular effects as seen with ATP infusion (31).
Fatigue resistance in repeated high intensity bouts of exercise is a much sought after attribute in athletics. This is true for both augmentation of training volume, as well as sustained force and power output in intermittent sports such as hockey. During fatiguing contractions acute adaptations in blood flow occur to stave off declines in force generating capacity (40, 45). There is a tight coupling between oxygen demand in skeletal muscle and increases in blood flow (45). Research suggests that it is red blood cells that regulate this response by acting as “oxygen sensors” (45). ATP is carried in red blood cells and when oxygen is low in a working muscle region, the red blood cell deforms resulting in a cascade of events which lead to ATP release and binding to endothelial cells in smooth muscle (43). Binding results in smooth muscle relaxation and subsequent increases in blood flow, nutrient and oxygen delivery (43). Specifically, extracellular ATP directly promotes the increased synthesis and release of nitric oxide (NO) and prostacyclin (PGl2) within skeletal muscle and therefore directly affects tissue vasodilation and blood flow (31). This is supported by research suggesting increased vasodilation and blood flow in response to intra-arterial infusion (47) and exogenous administration of ATP. These changes in blood flow likely lead to an increased substrate pool for skeletal muscle by virtue of increased glucose and O2 uptake (42). The outcome is maintenance of energy status in the cell under fatiguing contractions. (54, 56)
The physiological effects of ATP have led researchers to investigate the efficacy of oral supplementation of ATP (24). Jordan et al. (32) demonstrated that 225 mg per day of enteric-coated ATP supplementation for 15 days resulted in increased total bench press lifting volume (i.e. sets·repetitions·load) as well as within-group set-one repetitions to failure. More recently, Rathmacher et al. (52) found that 15 days of 400 mg per day of ATP supplementation increased minimum peak torque in set two of a knee extensor bout. Collectively the results discussed indicate that ATP supplementation maintains performance and increases training volume under high fatiguing conditions. However, greater fatigue increases recovery demands between training sessions.
Current evidence suggests that HMB acts by speeding regenerative capacity of skeletal muscle following high intensity or prolonged exercise (3). When training and/or diet are controlled, HMB can lower indices of skeletal muscle damage and protein breakdown in a dose-dependent fashion (50, 3, 2). Recently, HMB in a free acid form (HMB-FA) has been developed with improved bioavailability (18). Initial studies have shown that this form of HMB supplementation results in approximately double the plasma levels of HMB in about one-quarter the time after administration when compared with the presently available form, calcium HMB.
Further, HMB-FA given 30 minutes prior to an acute bout of high volume resistance training was able to attenuate indices of muscle damage and improve perceived recovery in resistance trained athletes (61). Moreover acute ingestion of 2.4 grams of HMB-FA increases skeletal muscle protein synthesis and decreases protein breakdown by +70% and −56% respectively (58).
A need exists for a composition and methods to increase strength and power and improve muscle mass. In addition, a need exists for a composition that prevents or lessens the typical decay seen in performance following an overreaching cycle. The present invention comprises a composition and methods of using a combination of ATP and HMB that results in these improvements.